Cancer is characterized as un-controlled proliferative disease. Most cancer cells proliferate more rapidly than their normal counter-partners. In the cell cycle division, chromosome duplication is essential and replication of DNA in S phase is tightly regulated. Inhibition of DNA replication is proved therapy for cancer treatment and inhibitors are widely used in clinic, for example, gemcitabine, active metabolites of 5-fluorouracil and Hydroxyurea (HU).
Cdc7 is evolutionally conserved serine/threonine kinase and plays important roles in initiation of DNA replication (Jiang W et al., EMBO J. 1999 Oct. 15; 18(20):5703-13). The kinase activity of cdc7 is regulated by binding with its activating partner. During the late G1 phase and the S phase, cdc7 forms a complex with Dbf4 (also known as ASK) and controls transition from the G1 phase to the S phase by phosphorylating its substrates (Masai H et al., J Cell Physiol. 2002 March; 190(3):287-96). Furthermore, recent studies report that cdc7 plays important roles in both DNA replication and DNA damage signaling pathways (Kim J M et al., Oncogene. 2008 May 29; 27(24):3475-82).
Recently, cdc7 kinase is getting a lot of attention as an attractive target for cancer therapy. Over-expression of cdc7 kinase is observed in multiple cancer cell lines and primary breast, colon, lung and other tumors (Bonte D et al., Neoplasia. 2008 Sep.; 10(9):920-31). Copy number of Dbf4 increases in some cell lines. In primary breast cancer, increased expressions of cdc7 and Dbf4 are highly correlated with loss of p53 activity. Interestingly, depletion of cdc7 kinase by siRNA results in different response between cancer cells and untransformed fibroblast cells. Depletion of cdc7 by siRNA causes the S-phase arrest and apoptosis in cancer cells, while normal fibroblast cells are arrested in G1 phase dependently on p53 activity (Montagnoli A et al., Cancer Res. 2004 Oct. 1; 64(19):7110-6.). Inhibition of DNA licensing checkpoint also causes similar phenotype to cdc7 inhibition (Shreeram S et. al., Oncogene. 2002 Sep. 26; 21(43):6624-32). Furthermore, cdc7 is activated in the cells under replication stress and depletion of cdc7 increased apoptosis induced by hydroxyurea or etoposide (Tenca P et al., J Biol. Chem. 2007 Jan. 5; 282(1):208-15.). Thus, inhibitor of cdc7 has utility in the cancer selective treatment, as either a single agent or in combination with other chemotherapeutic agents.
The following compounds are known as a compound having a cdc7 inhibitory action, whose structure is similar to those of the compound of the present invention.
1) Patent document 1 discloses the following compounds having cdc7, PKA and Akt inhibitory actions.

2) Patent document 2 discloses the following compound having cdc2 and cdc7 inhibitory actions.

wherein R is a hydrogen atom, amino, arylamino or the like;
R1 and R2 are each independently a hydrogen atom, a halogen atom, C1-6 alkyl, amino, arylamino or the like;
R3, R3′, R4 and R4′ are each independently a hydrogen atom, C1-6 alkyl, C3-6 cycloalkyl, a heterocyclic group or the like; and
R5 is a hydrogen atom, a halogen atom, C1-6 alkyl or the like.